A new ALK inhibitor is not a game changer, but an older one is!
Editorial Commentary

A new ALK inhibitor is not a game changer, but an older one is!

Beatriz Jimenez Munarriz1, Geoffrey Liu1, Sam Khan1,2

1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; 2Leicester Cancer Research Centre, University of Leicester, Leicester, UK

Correspondence to: Geoffrey Liu, MSc, MD. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Ave., Toronto, ON M5G 2M9, Canada. Email: geoffrey.liu@uhn.ca.

Comment on: Shi Y, Chen J, Yang R, et al. Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALKPositive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE). J Thorac Oncol 2024;19:912-27.

Keywords: Lung cancer; anaplastic lymphoma kinase-positive (ALK-positive); anaplastic lymphoma kinase inhibitors (ALK inhibitors)

Received: 17 June 2024; Accepted: 16 August 2024; Published online: 12 October 2024.

doi: 10.21037/actr-24-101

Lung cancer is the main cause of cancer mortality worldwide. Anaplastic lymphoma kinase (ALK)-fusions occur in approximately 5% of patients with advanced non-small cell lung cancer (NSCLC) and the introduction of tyrosine kinase inhibitors (TKIs) (1-4) has changed the treatment paradigm with excellent results in survival and quality of life (5).

Currently, several ALK-targeting TKIs (ALK-TKIs) are approved as first-line treatment for ALK-positive NSCLC: ceritinib (6), alectinib (7-12), brigatinib (13,14), ensartinib (15) (only for Chinese population) and lorlatinib (16-18). Due to significant improvement in progression free survival (PFS) and higher intracranial (IC) activity when compared to crizotinib, third generation TKIs are the preferred first-line treatment option.

Table 1 summarizes the outcomes of ALK-TKIs in first-line setting. Unfortunately, eventually most patients develop acquired resistance within a few years. Such resistance can be attributed to the occurrence of secondary mutations in the ALK tyrosine kinase domain, activated bypass signaling pathways, lineage changes (small or squamous cell transformation), amplification of ALK or drug efflux pumps (acquired resistance to crizotinib), and less commonly, primary ALK-TKI resistance (21).

Table 1

Clinical activity and toxicity of ALK TKIs in treatment-naïve ALK-rearranged metastatic NSCLC patients

TKI Study N ORR IC-ORR Cumulative CNS-progression mPFS (months) mOS (months) Grade 3–5 AEs (study drug vs. comparator) Most common TRAEs > G3 (study drug vs. comparator)
Crizotinib vs. CT PROFILE 1014 (1-4) 343 74% vs. 45% tBM 85% vs. 45%, HR 0.45; P=0.063 Not reported 10.9 vs. 7 BIRC, HR 0.45, P<0.001 NR vs. 47.5, HR 0.76, P=0.97, 4-year OS 56.6% vs. 49.1% 50.3% vs. 53.3% Elevated LFT 14% vs. 2%; vision disorders 1% vs. 0%; diarrhea 2% vs. 1%; edema 1% vs. 1%; vomiting 2% vs. 3%
Ceritinib vs. CT ASCEND-4 (6) 373 73% vs. 26.3% tBM 72.7% vs. 27.3% Not reported 16.6 vs. 8.1 BIRC, HR 0.55, P<0.00001 NR vs. 26.2, HR 0.73, P=0.56 78% vs. 62% Elevated ALT 31% vs. 3%; elevated AST 17% vs. 2%; diarrhea 5% vs. 1%; fatigue 4% vs. 3%
Alectinib vs. crizotinib ALEX 600 (7,8) 303 82.9% vs. 75.5% Prior RT: 85.7% vs. 71.4%. No prior RT: 78.6% vs. 40% 4.6% vs. 31.5% (12 months) 34.8 vs. 10.9 IA, HR 0.43, P<0.0001 NR vs. 57.4, HR 0.67, P=0.037, 5-year OS 62.5% vs. 45.5% 52% vs. 56.3% Elevated ALT 5% vs. 16%; elevated AST 5% vs. 10%; anemia 5.9% vs. 0.7%; creatinine increase 3.3% vs. 4%
J-ALEX 300 (9-11) 207 92% vs. 79% Not reported 5.9% vs. 16.8% 34.1 vs. 10.2 BIRC, HR 0.37, P<0.0001 5-year OS 60.9% vs. 64.1%, HR 1.03, P=0.91 26% vs. 52% Elevated CK 5% vs. 3%; interstitial lung disease 5% vs. 3%; rash 3% vs. 1%
ALESIA 600 (12) 187 91% vs. 77% 73% vs. 22% 12.4% vs. 37.4% (60 months), HR 0.16 41.6 vs. 11.1 IA, HR 0.3, P<0.0001 NR vs. NR, 5-year OS 66.4% vs. 56% 29% vs. 48% Elevated CK 5% vs. 3%; weight gain 3% vs. 2%; elevated ALT 2% vs. 7%
Brigatinib vs. crizotinib ALTA-1L (13,14) 275 74% vs. 62%, P=0.03 78% vs. 26%, P=0.001 10% vs. 43% (2 years), HR 0.25, P<0.0001 24 vs. 11.1 BIRC, HR 0.48, P<0.0001 NR vs. NR, 3-year OS 71% vs. 68%, HR 0.81, P=0.3 70% vs. 56% Elevated CK 24% vs. 1%; lipase increase 15% vs. 8%; hypertension 14% vs. 4%; amylase increase 6% vs. 1%
Ensartinib vs. crizotinib eXalt3 (15) 290 74% vs. 67% 63.3% vs. 21.1% 4.2% vs. 23.9% (12 months), HR 0.32, P=0.001 25.8 vs. 12.7 BIRC, HR 0.51, P<0.001 NR vs. NR, HR 0.91, P=0.73 44.8% vs. 35.6% Rash 11% vs. 0%; elevated ALT 4.2% vs. 7.5%; pruritus 2.1% vs. 0%; edema 2.1% vs. 2.1%
Lorlatinib vs. crizotinib CROWN (16-18) 296 76% vs. 58% 83% vs. 23% 5% vs. 64% (48 months), HR 0.02 NR vs. 9.1 IA, HR 0.19, P<0.0001, 5-year PFS 60% vs. 8% Not reported (not enough events) 77% vs. 57% Weight gain 17% vs. 0%; hypercholesterolemia 15% vs. 0%; hypertriglyceridemia 13% vs. 0%; hypertension 10% vs. 2%
Envonalkib vs. crizotinib NCT04009317 (19) 264 81.6% vs. 70.6%, P=0.056 78.9% vs. 23.8% 2.15% vs. 11.70%, P=0.0182 24.8 vs. 11.6 BIRC, HR 0.47, P<0.0001 NR vs. NR, 12-month OS 90.6% vs. 89.4% 55.7% vs. 42.8% Elevated ALT 15.2% vs. 6.7%, QTc prolongation 14.5% vs. 6.0%; elevated AST 9.9% vs. 2.2%; diarrhea 9.1% vs. 0%
Iruplinalkib vs. crizotinib INSPIRE (20) 292 93% vs. 89.3% 90.9% vs. 60% 3.2% vs. 12.2% (18 months) 27.7 vs. 14.6 BIRC, HR 0.34, P<0.0001 NE vs. NE, 2-year OS 85.6% vs. 84% 58.4% vs. 55% Hypertension 11.9% vs. 1.3%; elevated ALT 8.4% vs. 8.1%; elevated AST 6.3% vs. 5.4%

ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; ORR, overall response rate; IC, intracranial; CNS, central nervous system; mPFS, median progression free survival; mOS, median overall survival; AEs, adverse events; TRAEs, treatment-related adverse events; CT, chemotherapy; tBM, treated brain metastases; HR, hazard ratio; BIRC, blinded independent review committee; NR, not reached; OS, overall survival; LFT, liver function test; ALT, alanine transaminase; AST, aspartate aminotransferase; RT, radiotherapy; IA, investigator assessment; CK, creatine phosphokinase; PFS, progression free survival; QTc, heart-rate corrected QT interval on the electrocardiogram.

In this publication of the Journal of Thoracic Oncology, Shi and colleagues present the interim analysis of efficacy of the phase III, INSPIRE study (20), which randomized 292 treatment-naïve ALK-positive NSCLC to iruplinalkib vs. crizotinib in a Chinese population. Crossover was not allowed and patients were ineligible if they had received a previous ALK targeting TKI, though first line chemotherapy was acceptable. Iruplinalkib achieved the PFS-primary endpoint assessed by blinded independent review committee (BIRC) with a median PFS of 27.7 months when compared to 14.6 months with crizotinib [hazard ratio (HR) =0.34; 95% confidence interval (CI): 0.23–0.52; P<0.0001], and a 93% overall response rate (ORR) by BIRC (95% CI: 87.5–96.6%) vs. 89.3% (95% CI: 83.1–93.7%), respectively. This data is similar to the ALTA-1L study with brigatinib (PFS 24 months) (13,14) and eXalt3 with ensartinib (PFS 25.8 months), in which both trials allowed previous chemotherapy (15). In contrast, in the recently updated unplanned analysis after 5 years of follow-up of the CROWN trial, the PFS with lorlatinib remains not reached, and 60% of the intent-to-treat (ITT) population remains without tumor progression. Overall survival could not be reported because after 5 years, there were still too few total deaths across both arms to report, according to the CROWN protocol (18). With a future median PFS potentially doubling all other ALK-TKIs, lorlatinib dominates the landscape in the first-line setting (Figure 1); it will be interesting to see how fourth generation drugs such as NVL-655 will fare in this space.

Figure 1 Median PFS of a range of ALK-TKIs. IA and BIRC in first line treatment are reviewed (1-4,6-8,13-18,20,21). The PFS with lorlatinib remains not reached, and 60% of the ITT population remains without tumor progression. PFS, progression free survival; IA, investigator assessment; BIRC, blinded independent review committee; ALK, anaplastic lymphoma kinase; TKIs, tyrosine kinase inhibitors; ITT, intent-to-treat.

The HR for PFS in the INSPIRE trial favored iruplinalkib across most subgroups defined according to stratification factors, including central nervous system (CNS) metastasis at baseline, with a high IC-ORR of 90.9% with iruplinalkib compared to 60% with crizotinib. Moreover, the cumulative incidence of brain metastasis at 18 months ranks among the lowest (3.2% with iruplinalkib vs. 12.2% with crizotinib; HR =0.39; P=0.0081) (20). However, lorlatinib continues to report the lowest HR of 0.06 after an extended 5 years of follow-up with 92% of patients remaining free of IC progression by investigator assessment in the ITT population (18).

Regarding toxicity, most of the ALK-TKI have a similar safety profile, with gastrointestinal symptoms and laboratory abnormalities the most commonly observed side effects. However, there are some differences in class with a higher percentage of rash with ensartinib (15), myalgia on alectinib (7-11), diarrhea with brigatinib (13,14) or envonalkib (19), and hypertriglyceridemia with lorlatinib (16). The least desirable side effects are the neurological, mainly observed with lorlatinib, which includes a spectrum of cognitive effects reported in 26% of the patients, mood alterations in 17%, speech effects 5%, psychotic effects 5%, and peripheral neuropathy in 34% (16). However, neurotoxicity is particularly pronounced during the first 3 months of treatment, manageable with dose reductions, and the treatment discontinuation rate was 11%, of which only half were attributable treated related adverse events; these results are comparable to other TKIs for example alectinib (11%), and demonstrated that does not affect treatment efficacy. In addition, oncologists are gaining expertise on neurological side effect and guidelines regarding management will provide a more informed approach (22).

Lastly, the most important question regarding ALK-positive treatments is if more studies comparing with crizotinib are appropriate, given the current available data. In our opinion, no more trials should be using crizotinib as comparator given the robust data of new generation ALK-TKIs in PFS and CNS progression. Future studies should use the comparison with lorlatinib, which should be considered without doubt, the new gold standard treatment. The goals of any new ALK-targeting approaches should be dual; at least achieve similar efficacy as lorlatinib or better, while having an improved toxicity profile.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-101/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-101/coif). G.L. received grants to institution from NCI (US), CIHR (Canada), CCSRI (Canada), AstraZeneca, Takeda, Boehringer Ingelheim, AMGEN, EMD Serono, Pfizer, Bayer, payment/honoraria from AstraZeneca, Pfizer, EMD Serono, Takeda; and was on the Data Safety Monitoring Board or Advisory Board of AstraZeneca, Pfizer, EMD Serono, Merck, Abbvie, Jazz, Takeda, Anheart, Roche, BMS, Novartis, Lilly. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/actr-24-101
Cite this article as: Jimenez Munarriz B, Liu G, Khan S. A new ALK inhibitor is not a game changer, but an older one is! AME Clin Trials Rev 2024;2:86.

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